The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect. Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and bodily energy balance. We hypothesize that membrane potential modulation due to KATP channel opening in response to physiological workload limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Disruption of KATP channel function results in aggravated cellular calcium turnover, causing increased energy consumption and activation of protein kinase B (Akt) by calcium dependent calmodulin kinase. This insulin independent phosphorylation of Akt triggers a previously unrecognized muscle signaling cascade which could translate increased activity related energy consumption into adipose tissue mobilization. This proposal will directly study (1) the molecular mechanism of KATP channel control of activity-related energy consumption; (2) the mechanism of consequent adipose tissue mobilization and body weight reduction and (3) whether interference with skeletal muscle KATP channel function or downstream signaling cascades can be achieved while minimizing side-effects and disruption of muscle performance. The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related disease and future translational research.